Novel solid pharmaceutical dispersions

ABSTRACT

A novel solid pharmaceutical dispersion that improves the bioavailability of poorly water soluble drugs is produced by combining the drug with a polymer carrier such as polyvinylpyrrolidone. The drug is combined with the carrier without the need for using organic solvents or melting temperatures (fusion) through the use of a transition compound such as polyethylene glycol which partially solubilizes the drug and/or plasticizes the polymer.

BACKGROUND OF THE INVENTION

[0001] The bioavailabilities of many poorly water soluble drug entitiesare limited by their dissolution rates which in turn are governed by theparticle size and hence the specific surface area and/or the polymorphicstate of the active ingredient. At times, these problems are overcome byparticle size reduction. There are cases, however, where the dissolutionrates of the drug are not favorable enough to improve itsbioavailability. Therefore, techniques such as lyophilization, solventdeposition, solvate formation and solid dispersion have been employed toimprove the absorption of drugs.

[0002] A solid dispersion is a pharmaceutical formulation which may bedefined as “a dispersion of one or more active ingredients in an inertcarrier or matrix at solid state prepared by melting the two (fusion),dissolving them in a solvent, or a combination of approaches, i.e., aquasi melting-solvent method”. The solvent-based process uses organicsolvents to dissolve and intimately disperse the drug and carriermolecules. The process is relatively difficult. Identification of acommon solvent for both drug and carrier is a tedious exercise, andcomplete solvent removal from the product is, if at all possible, alengthy process. In addition, the volume of solvents required isexcessive, and the cost of solvent recovery systems is prohibitive. Thedrug and carrier are dissolved in a solvent such as methylene chloride,acetone, ethanol and mixtures thereof and the solvent is later removedby evaporation or the like while the drug/carrier solid dispersion iscollected as a powdered mass. Not only is the process lengthy andexpensive, but the use of organic solvents renders it hazardous andtoxic as well.

[0003] The second process for the manufacture of pharmaceuticaldispersions involves fusion of the two components where the drug and thecarrier are allowed to melt at temperatures at or above the meltingpoint of the drug. In the fusion process, the drug and carrier are firstblended and melted in a suitable mixer. The molten mixture is thencooled rapidly to provide a congealed mass which is subsequently milledto produce a powder. The fusion process is technically simple providedthat the drug and carrier are miscible in the molten state but this isnot always the case and furthermore, the process is limited in that ittends to lead to drug decomposition due to the high temperaturesrequired to melt the two components.

[0004] A third method that is used to produce a solid dispersion whenthere is difficulty with thermal instability and immiscibility betweenthe drug and the carrier is the hybrid fusion-solvent method. The drugis first dissolved in a small quantity of organic solvent and added tothe molten carrier. The solvent is then evaporated to generate a productthat is subsequently, milled to produce a powder. The pharmacokinetics,dissolution rates and processes for formulation of many different solidpharmaceutical dispersions is discussed at length in an article by Ford,J., in Pharm. Acta. Helv. 61, 3; 69-88 (1986).

[0005] It is an object of the present invention to describe a novelmanufacturing process for a solid pharmaceutical dispersion whichobviates the need for organic solvents, elevated melting temperatures orthe use of both. In particular, it is an object of the present inventionto produce a solid pharmaceutical dispersion by incorporating in theformulation a solubilizer/plasticizer which acts as a vehicle to reducethe transition temperature by partially solubilizing the drug and/orplasticizing the polymer. This is particularly useful in the formulationof solid pharmaceutical dispersions for drugs that decompose at or neartheir melting temperatures.

[0006] U.S. Pat. No. 4,803,081 to Falk et al. discloses an extendedrelease preparation of an active compound with very low solubilitywherein the compound is dispersed in a liquid or semi-solid non-ionicsolubilizer such as esters and ethers of polyethylene glycols. Thesolubilized drug is then combined with a hydrophilic gel system whichcontrols the release of the drug and solubilizer at a constant evenrate.

[0007] U.S. Pat. No. 4,689,235, to Barnes et al. discloses an extrudableencapsulation matrix which improves the loading capacity for oils,flavors, pharmaceuticals and the like. The matrix is comprised ofmaltodextrin and hydrogen octenylbutanedioate amylodextrin or itsequivalent. The formulation improves the extrusion processability of thedrug and enables high levels of active agent to be incorporated into thedosage form.

[0008] U.S. Pat. No. 4,678,516 to Alderman et al. teaches the formationof sustained release dosage forms utilizing a gel matrix comprised ofhydroxypropyl methyl cellulose (HPMC) and a major amount of aplasticizer in which the active pharmaceutical is dispersed. Suitableplasticizers include low molecular weight polyols such as ethyleneglycol, propylene glycol, polyethylene glycol and the like. Theplasticizer is employed to render the matrix thermoformable andcomprises a major amount thereof, i.e., at least 30%. The active agentmust be heat stable however, so that it is capable of being heated to atemperature sufficient to prepare a gel matrix from the HPMC and theplasticizer without being rendered inactive.

[0009] PCT Appln. No. WO 83/00091 teaches the formulation of a polymericdiffusion matrix for the sustained release of water insolublecardiovascular drugs such as 5-[(3,4-dimethoxyphenylethyl)methylamino]-2-(3,4 dimethoxyphenyl)-2-isopropyl valeronitirile.The matrix is comprised of a polar plasticizer, polyvinyl alcohol (PVA)and polyvinylpyrrolidone (PVP) in ratios of about 2:1:1 respectively.The cardiovascular pharmaceutical matrix is particularly useful intransdermal formulations wherein the drug is delivered at a constantsustained rate across the skin.

[0010] The present invention does away with the need for elaboratechemical matrices and increases the bioavailability of water insolubledrugs through the formation of a solid pharmaceutical dispersion. Thedispersion is formulated without the need of using organic solvents ormelting temperatures of drugs (fusion) which would otherwise decomposemany drugs which do so at or near their melting temperature.

SUMMARY OF THE INVENTION

[0011] The present invention is a novel pharmaceutical solid dispersionand the process for its preparation whereby generally water insolubledrugs are combined with a carrier polymer such as polyvinyl pyrrolidone(PVP) without the need for organic solvents and/or high fusiontemperatures. The process utilizes a vehicle such as polyethylene glycolwhich reduces the transition temperature and facilitates the molecularinteraction between the drug and a polymer such as polyvinyl pyrrolidone(PVP) by partially solubilizing the drug and/or plasticizing thepolymer. This allows for a continuous and well controlled processingmode of manufacture.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The solid pharmaceutical dispersions of the present inventionincrease the bioavailability of various water insoluble drugs byincreasing their dissolution rates which in turn produce increases inboth the rates and extent of the drugs absorption. Hence, the dosage ofmany solid dispersed drugs can be decreased and it is also believed thatdue to the increased dissolution and associated rapid absorption mayreduce the proportion of the drug that is metabolized presystematically.

[0013] Nearly any water-insoluble drug may be formulated in the practiceof the present invention so as to increase its solubility and hence itsbioavailability. Drugs that are particularly useful in the practice ofthe present invention are those that decompose at or near their meltingtemperature since these certainly cannot be formulated into solidpharmaceutical dispersions using the fusion method. Suitablepharmaceuticals include, but are not limited to acetohexamide,ajamaline, amylobarbitone, bendrofluozide, benzbromarone, benzonatate,benzylbenzoate, betamethasone, chloramphenicol, chlorpropamide,chlorthalidone, clofibrate, corticesteroids, diazepam, dicumerol,digitoxin, dihydroxypropyltheophylline, ergot alkaloids, ethotoin,frusemide, glutethimide, griseofulvin, hydrochlorothiazide,hydrocortisone, hydroflumethiazide, hydroquinone, hydroxyalkylxanthines,indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin,meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin,novalgin, nystatin, papaverine, paracetamol, phenylbutazone,phenobarbitone, prednisolone, prednisone, primadone, reserpine,romglizone, salicylic acid, spiranolactone, sulphabenzamide,sulphadiamadine, sulphamethoxydiazine, sulphamerazine,succinylsulphathiazole, sulphamethizole, sulphamethoxazole,sulphathiazole, sulphisoxazole, testosterone, tolazoline, tolbutamide,trifluoperazine, trimethaprim and other water insoluble drugs.

[0014] Suitable carrier polymers that are useful in the formation of thesolid drug dispersion include, but are not limited to,polyvinylpyrrolidone (PVP), high molecular weight polyethylene glycol(PEG), urea, citric acid, vinyl acetate copolymer, Eudragit® acrylicpolymers, succinic acid, sugars and mixtures thereof. The carrier ofchoice obviously is dependent upon the drug to be dispersed butgenerally the chosen carrier must be pharmacologically inert andchemically compatible with the drug in the solid state. They should notform highly bonded complexes with a strong association constant and mostimportantly should be freely water soluble with intrinsic rapiddissolution properties.

[0015] Preferably, the carrier of choice in most dispersions ispolyvinylpyrrolidone (PVP) which is a polymer of the monomeric unit(C₆H₉NO)_(n) and is a free flowing amorphous powder that is soluble inboth water and organic solvents. It is hygroscopic in nature andcompatible with a wide range of hydrophilic and hydrophobic resins.Another preferred carrier is a high molecular weight polyethylene glycolsuch as (PEG) 6000 which is a condensation polymer of ethylene glycolwith the general formula (HOCH₂(CH₂OCH₂))_(n)CH₂OH. Polyethylene glycolsare generally a clear, colorless, odorless viscous liquid to waxy solidthat is soluble or miscible with water.

[0016] The surprising and unexpected results of the present invention isthe creation of a solid pharmaceutical dispersion comprised of theaforementioned water insoluble drugs and carriers without the need forusing organic solvents, fusion (heat) or both (solvent/heat) which areeither lengthy and expensive methods or which limit the types of drugsthat can be formulated, i.e. heat labile drugs. Surprisingly, it wasdiscovered that the addition of a plasticizer/solubilizer during themixing of the two components results in a chemical environment thatreadily lends itself to dispersion formation.

[0017] Suitable plasticizers/solubilizers useful in the practice of thepresent invention include low molecular weight polyethylene glycols suchas PEG 200, PEG 300, PEG 400 and PEG 600. Other suitable plasticizersinclude propylene glycol, glycerin, triacetin, triethyl citrate, andsugar alcohols such as sorbitol, mannitol, and mixtures thereof.Optionally, a surfactant such as Tween 80 may be added to facilitatewettability within the formulation.

[0018] The water insoluble drug of interest is first blended with thecarrier using any appropriate mixer in a drug/carrier ratio of fromabout 1:9 to about 5:1 respectively, based upon a percentage weightbasis. Preferably, the drug/carrier ratio will be approximately 3:1 toabout 1:3, respectively. The blend is then transferred to a fluid bedgranulator and a plasticizer such as PEG 400 is dissolved in water witha surfactant such as Tween 80, if necessary. Other suitable surfactantsinclude Tweens 20 and 60, Span 20, Span 40, Pluronics, polyoxyethylenesorbitol esters, nionoglycerides, polyoxyethylene acids, polyoxyethylenealcohols and mixtures thereof. Once both ingredients are sufficientlydissolved, the solution is sprayed onto the powder blend in the fluidbed granulator under specific conditions. The resultant granulation istransferred to a container and fed into a high intensity mixer such as atwin screw extruder with at least one, and preferably more than oneheating zones. The mixture is then extruded at appropriate temperaturesdepending on the heat stability of the drug until a solid dispersion iscollected as an extrudate which is then transferred to a drum formilling. The solid pharmaceutical dispersion is then ground into apowdery mass and further prepared in a tablet or capsule form which maybe optionally coated with a film such as hydroxypropyl methyl celluloseif desired.

[0019] The following examples are given to more particularly set forthand teach several specifics of the present invention. It must beremembered that they are for illustrative purposes only and should notbe construed in a manner that will limit the spirit and scope of theinvention as recited by the claims that follow:

EXAMPLE 1

[0020] Romglizone, whose chemical name is(+)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)-benzyl]-2,4-thiazolidinedione,is a novel insulin-sensitizing drug being developed for the treatment ofnon-insulin-dependent diabetes mellitus. The chemical structure of thedrug is as follows:

[0021] The drug is practically insoluble in water. Its solubilityslightly increases as the pH of the aqueous media increases. In vivostudies involving animal models showed that the drug has poorbioavailability when administered in its original crystalline form. Incontrast, when an equivalent solid dispersion of the drug inpolyvinylpyrrolidone (PVP) was given, the bioavailability of the drugimproved significantly.

[0022] Romglizone (500 gm.) and polyvinylpyrrolidone (PVP) (300 gm.)were blended in P-K blender (Make, Model) for eight (8) minutes andsubsequently transferred to a fluid bed granulator. Simultaneously, asurfactant such as Tween 80 (30 gm.) was dissolved with polyethyleneglycol 400 (75 gm.) in a sufficient amount of water for completedissolution. The Tween/PEG/H₂O solution was then sprayed onto thedrug/PVP blend in a Roto-Glatt GPCG-5 fluid bed granulator at 36-40° C.until the solution is exhausted. The resultant granulation was then fedinto a twin screw extruder with four heating zones set at 125° C., 125°C., 125° C. and 115° C. respectively. The solid dispersion is extrudedat a rate of five gms/sec at a head pressure no greater than 5,000p.s.i. and collected in a drum containing a dessicant such as selicagel. The collected extrudate was then milled using a standard mill suchas a Fitzmill to produce a fine powdery mass of the Romglizone soliddispersion.

EXAMPLE II

[0023] A batch of solid pharmaceutical dispersion comprising Romglizonewas made according to the procedure set forth in Example I using thefollowing materials and proportions. Values given refer to the amount ofingredients in a single tablet. Romglizone 200.00 mgPolyvinylpyrrolidone 120.00 mg Tween 80 NF 12.00 mg Polyethylene glycol400 NF 30.00 mg Purified H₂O USP 42.60 mg

EXAMPLE III

[0024] The solid phamaceutical dispersion of Example II was furtherprocessed into a tablet core by first thoroughly mixing approximately362.0 gm. of the milled material with 10.00 mg. of Cab-O-Sil. Theresultant mixture was then discharged into a P-K blender and thefollowing materials were then added. Talc USP 4.00 mg. MicrocystallineCellulose NE 29.00 mg. Low substituted Hydroxypropyl 120.00 mg.Cellulose (L-HPC)

[0025] The materials were tumble blended for approximately ten (10)minutes after which a portion of the blend was discharged into a plasticbag. Magnesium stearate (5.00) gm. was added to the contents of the bagand the ingredients were mixed well. The mix was then passed through aNo. 30 U.S. standard mesh screen, and added to the main blend. Themixture was again tumble-blended for an additional three minutes. Thefinal blend was then compressed into tablet form using a standardcapsule-shaped plain punch known in the art. The tabletted soliddispersion may then be optionally film coated with hydroxypropylmethylcellulose using a standard pan coating apparatus.

What we claim is:
 1. A process for the preparation of a poorly watersoluble drug in solid dispersion comprising a) blending the drug with acarrier; b) dissolving a surfactant and a plasticizer/solubilizer inwater; c) spraying the surfactant-plasticizer/solubilizer solution ontothe drug/carrier mixture in a fluid bed granulator; d) extruding theresulting granulation through a twin screw extruder with at least oneheating zone; and, e) milling the extrudate to a powdery mass of thesolid drug dispersion.
 2. The process of claim 1 wherein said drug isselected front the group consisting of acetohexamide, ajamaline,amylobarbitone, bendrofluozide, benzbromarone, benzonatate,benzylbenzoate, betamethazone, chloramphenicol, chlorpropamide,chlorthalidone, clofibrate, corticesteroids, diazepam, dicumerol,digitoxin, dihydroxypropyltheophylline, ergot alkaloids, ethotoin,frusemide, glutethimide, griseofulvin, hydrochlorothiazide,hydrocortisone, hydroflumethiazide, hydroquinone, hydroxyalkylxanthines,indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin,meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin,novalgin, nystatin, papaverine, paracetamol, phenylbutazone,phenobarbitone, prednisolone, prednisone, primadone, reserpine,romglizone, salicylic acid, spiranolactone, sulphabenzamide,sulphadiamadine, sulphamethoxydiazine, sulphamerazine,succinylsulphathiazole, sulphamethizole, sulphamethoxazole,sulphathiazole, sulphisoxazole, testosterone, tolazoline, tolbutamide,trifluoperazine, trimethaprim and mixtures thereof.
 3. The process ofclaim 2 wherein said carrier is selected from the group consisting ofpolyvinyl pyrrolidone, high molecular weight polyethylene glycol, urea,citric acid, vinyl acetate copolymer, Eudragit® acrylic polymers,succinic acid, sugars and mixtures thereof.
 4. The process of claim 3wherein said plasticizer/solubilizer is selected from the groupconsisting of low molecular weight polyethylene glycol, propyleneglycol, glycerin, triacetin, triethyl citrate, sugar alcohols andmixtures thereof.
 5. The process of claim 4 wherein said surfactant isselected from the group consisting of Tween, Span, Pluronics,polyoxyethylene sorbitol esters, monodiglycerides, polyoxyethylene acidpolyoxyethylene alcohol and mixtures thereof.
 6. The process of claim 5wherein said granulation is extruded at a temperature less than thedecomposition point of said drug.
 7. The process of claim 6 wherein saiddrug and carrier are mixed in ratios of from about 1:9 to about 5:1respectively, on a percent weight basis.
 8. The process of claim 7wherein said drug and carrier are mixed in a ratio of from about 3:1 toabout 1:3 respectively, on a percent weight basis.
 9. A solidpharmaceutical dispersion with improved solubility characteristicsconsisting essentially of a poorly water soluble drug and; a) a carrierselected from the group consisting of polyvinyl pyrrolidone, highmolecular weight polyethylene glycol, urea, citric acid, Eudragit®acrylic polymers, succinic acid and mixtures thereof and, b) asolubilizer/plasticizer selected from the group consisting of polyols,phthalate esters, glycerol esters, citrate esters, sugar alcohols andmixtures thereof.
 10. The solid pharmaceutical dispersion of claim 9wherein said poorly water soluble drug is selected from the groupconsisting of acetohexamide, ajamaline, amylobarbitone, bendrofluozide,benzbromarone, benzonatate, benzylbenzoate, betamethazone,chloramphenicol, chlorpropamide, chlorthalidone, clofibrate,corticesteroids, diazepam, dicumerol, digitoxin,dihydroxypropyltheophylline, ergot alkaloids, ethotoin, frusemide,glutethimide, griseofulvin, hydrochlorothiazide, hydrocortisone,hydroflumethiazide, hydroquinone, hydroxyalkylxanthines, indomethacin,isoxsuprine hydrochloride, ketoprofen, khellin, meprobamate, nabilone,nicotainamide, nifedipine, nitrofurantoin, novalgin, nystatin,papaverine, paracetamol, phenylbutazone, phenobarbitone, prednisolone,prednisone, primadone, reserpine, romglizone, salicylic acid,spiranolactone, sulphabenzamide, sulphadiamadine, sulphamethoxydiazine,sulphamerazine, succinylculphathiazole, sulphamethizole,sulphamethoxazole, sulphathiazole, sulphisoxazole, testosterone,tolazoline, tolbutamide, trifluoperazine, trimethaprim and mixturesthereof.
 11. The solid pharmaceutical dispersion of claim 10 whereinsaid drug and carrier are formulated in ratios of from about 1:9 toabout 5:1 respectively, on a percentage weight basis.
 12. The solidpharmaceutical dispersion of claim 11 wherein said drug and said carrierare formulated in ratios of from about 3:1 to about 1:3, respectively ona percentage weight basis.
 13. A solid pharmaceutical dispersion withimproved solubility characteristics comprised of a poorly water solubledrug and a carrier produced by the process consisting of: a) mixing saiddrug and the carrier in a ratio of approximately 1:9 to about 5:1respectively, on a percent weight basis; b) spraying onto said mixture asolution consisting of a plasticizer/solubilizer, and optionally, asurfactant; c) extruding the resultant granulation in a twin screwextruder with at least one heating zone; and d) milling the extrudate toa powdery mass.
 14. The solid pharmaceutical dispersion of claim 13wherein said drug is selected from the group consisting ofacetohexamide, ajamaline, amylobarbitone, bendrofluozide, benzbromarone,benzonatate, benzylbenzoate, betamethazone, chloramphenicol,chlorpropamide, chlorthalidone, clofibrate, corticesteroids, diazepam,dicumerol, digitoxin, dihydroxypropyltheophylline, ergot alkaloids,ethotoin, frusemide, glutethimide, griseofulvin, hydrochlorothiazide,hydrocortisone, hydroflumethiazide, hydroquinone, hydroxyalkylxanthines,indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin,meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin,novalgin, nystatin, papaverine, paracetamol, phenylbutazone,phenobarbitone, prednisolone, prednisone, primadone, reserpine,romglizone, salicylic acid, spiranolactone, sulphabenzamide,sulphadiamadine, sulphamethoxydiazine, sulphamerazine,succinylsulphathiazole, sulphamethizole, sulphamethoxazole,sulphathiazole, sulphisoxazole, testosterone, tolazoline, tolbutamide,trifluoperazine, trimethaprim and mixtures thereof.
 15. The solidpharmaceutical dispersion of claim 14 wherein said carrier is selectedfrom the group consisting of polyvinyl pyrrolidone, high molecularweight polyethylene glycol, urea, citric acid, vinyl acetate copolymer,Eudragit® acrylic polymers, succinic acid, sugars and mixtures thereof.16. The solid pharmaceutical disperson of claim 15 wherein saidplasticizer/solubilizer is selected from the group consisting of lowmolecular weight polyethylene glycol, propylene glycol, glycerin,triacetin, triethyl citrate, sugar alcohols and mixtures thereof. 17.The solid pharmaceutical dispersion of claim 16 wherein said surfactantis selected from the group consisting of Tween, Span, Pluronics,polyoxyethylene sorbitol esters, polyoxyethylene acid, polyoxyethylenealcohols and mixtures thereof.
 18. The solid pharmaceutical dispersionof claim 17 wherein said extrusion is carried out at a temperature belowthe decomposition point of said drug.
 19. The solid pharmaceuticaldispersion of claim 18 wherein said extrusion occurs at a rate ofapproximately 2 gm/sec. to about 7 gm/sec.